Open questions in the NF-KB field

A variety of stress signals leads to activation of the inducible transcription factor NF-KB, one of the master regulators of the innate immune response. Despite a wealth of information available on the NF-KB core components and its control by different activation pathways and negative feedback loops, several levels of complexity hamper our understanding of the system. This has also contributed to the limited success of NF-KB inhibitors in the clinic and explains some of their unexpected effects. Here we consider the molecular and cellular events generating this complexity at all levels and point to a number of unresolved questions in the field. We also discuss potential future experimental and computational strategies to provide a deeper understanding of NF-KB and its coregulatory signaling networks.